International Journal of Pharmaceutics最新文献_第9页

Characterisation of colloidal structures and their solubilising potential for BCS class II drugs in fasted state simulated intestinal fluid 空腹状态模拟肠液中 BCS II 类药物胶体结构及其增溶潜力的特征。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-09-22 DOI: 10.1016/j.ijpharm.2024.124733

A suite of fasted state simulated intestinal fluid (SIF), based on variability observed in a range of fasted state human intestinal fluid (HIF) samples was used to study the solubility of eight poorly soluble drugs (three acidic drugs (naproxen, indomethacin and phenytoin), two basic drugs (carvedilol and tadalafil) and three neutral drugs (felodipine, fenofibrate, griseofulvin)). Particle size of the colloidal structures formed in these SIF in the presence and absence of drugs was measured using dynamic light scattering and nanoparticle tracking analysis.

Results indicate that drug solubility tends to increase with increasing total amphiphile concentration (TAC) in SIF with acidic drugs proving to be more soluble than basic or neutral drug in the media evaluated. Dynamic light scattering showed that as the amphiphile concentration increased, the hydrodynamic diameters of the structures decreased. The scattering distribution confirmed the polydispersity of the simulated intestinal fluids compared to the monodisperse distribution observed for FaSSIF v1). There was a large difference in the size of the structures found based on the composition of the SIF, for example, the diameter of the structures measured in felodipine in the minimum TAC media was measured to be 170 ± 5 nm which decreased to 5.1 ± 0.2 nm in the maximum TAC media point. The size measured of the colloidal structures of felodipine in the FaSSIF v1 was 86 ± 1 nm. However, there was no simple correlation between solubility and colloidal size.

Nanoparticle tracking analysis was used for the first time to characterise colloidal structures within SIF and the results were compared to those obtained by dynamic light scattering. The particle size measured by dynamic light scattering was generally greater in media with a lower concentration of amphiphiles and smaller in media of a higher concentration of amphiphiles, compared to that of the data yielded by nanoparticle tracking analysis.

This work shows that the colloidal structures formed vary depending on the composition of SIF which affects the solubility. Work is ongoing to determine the relationship between colloidal structure and solubility.

根据在一系列空腹状态人体肠液（HIF）样本中观察到的变异性，我们使用了一套空腹状态模拟肠液（SIF）来研究八种溶解性较差的药物（三种酸性药物（萘普生、吲哚美辛和苯妥英）、两种碱性药物（卡维地洛和他达拉非）和三种中性药物（非洛地平、非诺贝特和格列齐特））的溶解性。使用动态光散射和纳米粒子跟踪分析法测量了药物存在和不存在时在这些 SIF 中形成的胶体结构的粒度。结果表明，药物溶解度随着 SIF 中两性化合物总浓度（TAC）的增加而增加，在所评估的介质中，酸性药物的溶解度高于碱性或中性药物。动态光散射显示，随着双亲化合物浓度的增加，结构的流体力学直径减小。散射分布证实了模拟肠液的多分散性，而在 FaSSIF v1) 中观察到的是单分散分布。根据 SIF 的组成，所发现的结构大小差异很大，例如，在最小 TAC 介质中测得的非洛地平结构直径为 170 ± 5 nm，而在最大 TAC 介质点中则降至 5.1 ± 0.2 nm。在 FaSSIF v1 中测得的非洛地平胶体结构尺寸为 86 ± 1 nm。然而，溶解度和胶体大小之间并没有简单的相关性。我们首次使用纳米粒子跟踪分析法对 SIF 中的胶体结构进行了表征，并将结果与动态光散射法得出的结果进行了比较。与纳米粒子跟踪分析得出的数据相比，动态光散射法测得的粒径通常在两亲化合物浓度较低的介质中较大，而在两亲化合物浓度较高的介质中较小。这项工作表明，形成的胶体结构因 SIF 的成分而异，而 SIF 的成分会影响溶解度。确定胶体结构与溶解度之间关系的工作正在进行中。

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引用次数: 0

Excipient effects on supersaturation, particle size dynamics, and thermodynamic activity of multidrug amorphous formulations 辅料对多药无定形制剂的过饱和度、粒度动力学和热力学活性的影响。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-09-21 DOI: 10.1016/j.ijpharm.2024.124738

Multidrug formulations enhance patient compliance and extend the life cycle of pharmaceutical products. To overcome solubility challenges for multidrug combinations, amorphous formulations are commonly used. However, the excipients for creating amorphous formulations are often selected without an understanding of their effects on the bioavailability of the drugs. In this context, we investigated the impact of three types of excipients (polymers, surfactants and amino acids) on the supersaturation and thermodynamic activity of multidrug amorphous formulations. Additionally, we studied the particle size dynamics of the colloidal phase formed as a result of liquid–liquid phase separation. The amorphous solubility of two drugs, atazanavir and ritonavir, was determined in solutions containing predissolved excipients and the particle size dynamics of the colloidal particles was measured by dynamic light scattering. Dissolution experiments of atazanavir and ritonavir were conducted in predissolved sodium dodecyl sulfate (SDS), an anionic surfactant, and alanine solutions under non-sink conditions. Membrane transport of the drugs was evaluated using a MicroFLUX setup. The polymers had only minor effects on the amorphous solubility, but SDS significantly increased the solubilities of both drugs. In contrast, the other non-ionic surfactants and amino acids reduced the solubility of atazanavir but had no negative effect on ritonavir. Polymers were effective in maintaining supersaturation and preventing the coarsening of the colloidal particles. Conversely, alanine was neither able to inhibit the solution crystallization nor increase the flux of either drug. Despite the increase in the amorphous solubility of both drugs in SDS, flux was reduced. These results highlight the importance of properly selecting excipients for supersaturating amorphous formulations. The choice of excipient impacts the thermodynamic activity, the phase behaviour of the drugs and hence, the resulting absorption after oral intake.

多药制剂可提高患者的依从性，延长药品的生命周期。为了克服多药复方制剂在溶解度方面的难题，通常采用无定形制剂。然而，在选择制作无定形制剂的辅料时，往往不了解它们对药物生物利用度的影响。在这种情况下，我们研究了三种辅料（聚合物、表面活性剂和氨基酸）对多药无定形制剂的过饱和度和热力学活性的影响。此外，我们还研究了液-液相分离后形成的胶体相的粒度动态。我们测定了阿扎那韦和利托那韦两种药物在含有预溶解辅料的溶液中的无定形溶解度，并通过动态光散射测量了胶体颗粒的粒度动态。在非沉降条件下，在预先溶解的十二烷基硫酸钠（SDS）（一种阴离子表面活性剂）和丙氨酸溶液中进行了阿扎那韦和利托那韦的溶解实验。使用 MicroFLUX 装置对药物的膜传输进行了评估。聚合物对无定形溶解度的影响很小，但 SDS 能显著提高两种药物的溶解度。相比之下，其他非离子表面活性剂和氨基酸降低了阿扎那韦的溶解度，但对利托那韦没有负面影响。聚合物能有效维持过饱和度，防止胶体颗粒变粗。相反，丙氨酸既不能抑制溶液结晶，也不能增加两种药物的通量。尽管两种药物在 SDS 中的无定形溶解度都有所增加，但通量却有所降低。这些结果凸显了为过饱和无定形制剂正确选择辅料的重要性。辅料的选择会影响药物的热力学活性和相行为，进而影响口服后的吸收。

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引用次数: 0

Investigation of the dissolution rate and oral bioavailability of atenolol-irbesartan co-amorphous systems 阿替洛尔-厄贝沙坦共晶体系的溶出率和口服生物利用度研究

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-09-21 DOI: 10.1016/j.ijpharm.2024.124704

Irbesartan (IBS), a common drug to treat hypertension, has poor oral bioavailability because of its limited aqueous solubility. Recently, co-amorphous systems (CAMs) have demonstrated the ability to improve the solubility of poorly water-soluble drugs. In this study, IBS was co-amorphized with a pharmacologically relevant drug atenolol (ATL) by melt-quenching. The structures of the resulting ATL-IBS CAMs, which were formulated in molar ratios of 2:1, 1:1, 1:2 and 1:4, were characterized by the polarizing microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier-infrared transform spectroscopy. ATL-IBS CAM_1:1 showed higher IBS dissolution than crystalline IBS, amorphous IBS (IBS AM) and the other CAMs. The results of the supersaturated solution stability showed that ATL enhanced the supersaturation maintenance of IBS by extensive interactions. The CAMs exhibited excellent physical stability at 25°C/60% RH. The pharmacokinetics experiments showed that the relative oral bioavailability of IBS was 2.78-fold higher than bulk IBS (p < 0.001) after oral administration of ATL-IBS CAM_1:1 to rats. The results of this study demonstrate that CAMs provide an alternative option for the development of fixed dose combination of ATL and IBS.

厄贝沙坦（IBS）是一种治疗高血压的常用药物，由于其水溶性有限，口服生物利用度较低。最近，共晶体系（CAMs）已证明能够改善水溶性差的药物的溶解度。在这项研究中，通过熔融淬火将 IBS 与药理相关药物阿替洛尔（ATL）进行了共变形。通过偏光显微镜、粉末 X 射线衍射、差示扫描量热法和傅里叶红外光谱法对所制备的 ATL-IBS CAMs（摩尔比分别为 2:1、1:1、1:2 和 1:4）的结构进行了表征。ATL-IBS CAM1:1 比结晶 IBS、无定形 IBS（IBS AM）和其他 CAM 显示出更高的 IBS 溶解度。过饱和溶液稳定性结果表明，ATL 通过广泛的相互作用增强了 IBS 的过饱和度维持能力。在 25 °C/60 % 相对湿度条件下，CAMs 表现出优异的物理稳定性。药代动力学实验表明，IBS 的相对口服生物利用度是散装 IBS 的 2.78 倍（对大鼠的比值为 1:1）。研究结果表明，CAMs 为开发固定剂量的 ATL 和 IBS 复方制剂提供了另一种选择。

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引用次数: 0

Intelligent response micelles with high andrographolide loading for the effective treatment of atherosclerosis 有效治疗动脉粥样硬化的高穿心莲内酯智能反应胶束。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-09-21 DOI: 10.1016/j.ijpharm.2024.124705

Atherosclerosis (AS) is a chronic inflammatory disease which associated with a maladaptive immune response driven by macrophages. In the development of AS, macrophages have gradually become new therapeutic targets due to their involvement in numerous inflammatory-related pathological processes in AS. However, despite significant breakthroughs in the development of macrophages targeting nanocarriers, unsatisfactory drug loading, and inexact drug release limited the development of nano-therapy. Therefore, developing a high drug-loading nanocarrier that can accurately release drugs at AS lesions is quite essential. Herein, we optimized double moieties coupled mPEG-PLA copolymer micelles via phenylboronic acid (PBA)-terminated on the hydrophobic chain and cRGD coupled in hydrophilic chain to enhance AS therapy. The micelles loaded with andrographolide (AND) exhibited advanced drug loading capacity, as PBA could form a reversible boronic ester with AND at physiological pH. The cRGD-modified AND-loaded micelles (RPPPA) could be efficaciously internalized by macrophages and efficiently prevent macrophages from differentiating to foam cells. After intravenous administration, RPPPA could accumulate in plaques and exert therapeutic effects. The optimistic therapeutic results of atherosclerosis were shown in RPPPA, included the fewer plaques, a smaller necrotic core, a more stabilized fibrous cap, and lower macrophages and MMP-9, compared with the control group. To sum up, the proposed encouraging therapy can contribute to high drug loading, exact target, and precise drug release as well as reduce inflammation for AS treatment.

动脉粥样硬化（AS）是一种慢性炎症性疾病，与巨噬细胞驱动的不良免疫反应有关。在动脉粥样硬化的发展过程中，巨噬细胞参与了许多与炎症相关的病理过程，因此逐渐成为新的治疗靶点。然而，尽管巨噬细胞靶向纳米载体的开发取得了重大突破，但药物载量不理想、药物释放不精确等问题限制了纳米疗法的发展。因此，开发一种能在强直性脊柱炎病变部位准确释放药物的高药物负载纳米载体就显得尤为重要。在此，我们通过在疏水链上以苯硼酸（PBA）为末端、在亲水链上以cRGD为末端的双分子偶联mPEG-PLA共聚物胶束进行了优化，以提高强直性脊柱炎的治疗效果。由于 PBA 能在生理 pH 值下与 AND 形成可逆的硼酸酯，因此负载穿心莲内酯（AND）的胶束表现出较高的载药能力。经 cRGD 修饰的 AND 负载胶束（RPPPA）可被巨噬细胞有效内化，并能有效防止巨噬细胞分化为泡沫细胞。静脉给药后，RPPPA 可在斑块中聚集并发挥治疗作用。与对照组相比，RPPPA 对动脉粥样硬化的治疗效果非常乐观，包括斑块更少、坏死核心更小、纤维帽更稳定、巨噬细胞和 MMP-9 更低。总之，所提出的鼓励性疗法有助于实现高载药量、精确靶点、精确释药和减少炎症，从而达到治疗强直性脊柱炎的目的。

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引用次数: 0

Controlled release of doxorubicin from Poly-(D,L-lactide-co-glycolide) (PLGA) nanoparticles prepared by coaxial electrospraying 同轴电喷雾法制备的聚-(D,L-乳酸-共聚乙二醇)（PLGA）纳米粒子可控释放多柔比星。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-09-21 DOI: 10.1016/j.ijpharm.2024.124724

Enhancing the efficacy and reducing the toxicity of chemotherapeutic agents like doxorubicin (DOX) is crucial in cancer treatment. Core-shell nanoparticles (NPs) fabricated by coaxial electrospraying offer controlled release of anticancer agents with the polymer shell protecting drug molecules from rapid degradation, prolonging therapeutic effect. This study developed DOX-loaded poly(lactic-co-glycolic acid) (PLGA) NPs. NPs were fabricated with matrix or core–shell structure via single needle or coaxial electrospraying, respectively. Core-shell NPs exhibited high encapsulation efficiency (>80 %) with controlled DOX distribution. Compared to matrix NPs, core–shell NPs demonstrated slower sustained release (69 % in 144 h) after reduced initial burst (22 % in 8 h). Release kinetics followed a diffusion mechanism when compared to free drug and matrix DOX-loaded NPs. In vitro assays showed core–shell NPs’ enhanced cytotoxicity against breast cancer cells MCF-7, with higher uptake observed by fluorescence microscopy and flow cytometry. The IC₅₀ for core-shell NPs displayed a significant drop (0.115 μg/mL) compared to matrix NPs (0.235 μg/mL) and free DOX (1.482 μg/mL) after 72 h. Coaxial electrospraying enables the production of therapeutically advantageous core–shell NPs, offering controlled drug release with high encapsulation efficiency, potentially improving clinical anticancer chemotherapy.

提高多柔比星（DOX）等化疗药物的疗效并降低其毒性对癌症治疗至关重要。通过同轴电喷法制造的核壳纳米粒子（NPs）可控制抗癌药物的释放，其聚合物外壳可保护药物分子不被快速降解，从而延长治疗效果。本研究开发了负载 DOX 的聚（乳酸-共聚乙醇酸）（PLGA）NPs。通过单针或同轴电喷法分别制备了基质或核壳结构的 NPs。核壳 NPs 具有很高的包封效率（>80%），并能控制 DOX 的分布。与基质 NPs 相比，核壳 NPs 在减少初始猝灭（8 小时内释放 22%）后，表现出更慢的持续释放速度（144 小时内释放 69%）。与游离药物和基质 DOX 负载 NPs 相比，释放动力学遵循扩散机制。体外实验表明，核壳 NPs 对乳腺癌细胞 MCF-7 的细胞毒性增强，荧光显微镜和流式细胞仪观察到的吸收率更高。72 小时后，与基质 NPs（0.235 μg/mL）和游离 DOX（1.482 μg/mL）相比，核壳 NPs 的 IC50 显著下降（0.115 μg/mL）。同轴电喷雾技术能够生产出具有治疗优势的核壳 NPs，药物释放可控且封装效率高，有望改善临床抗癌化疗。

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引用次数: 0

Development of levamlodipine long-acting patches based on an ion-pair strategy: Investigation of the mechanism for reducing skin irritation 基于离子对策略开发左旋氨氯地平长效贴剂：研究减少皮肤刺激的机制。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-09-21 DOI: 10.1016/j.ijpharm.2024.124703

The aim of this study was to develop a long-acting transdermal patch of levamlodipine (LAM) using an ion-pair strategy to reduce the skin irritation induced by topical application of LAM and explore the mechanism underlying the improvement of skin irritation. The formulation was optimized through porcine in vitro transdermal experiments and rabbit in vivo skin irritation tests. The obtained formulation consisted of poly (2-Ethylhexyl acrylate-co-N-Vinyl-2-pyrrolidone-co-N-(2-Hydroxyethyl) acrylamide) (PENH) as the adhesive matrix, 13.00 % levamlodipine-sorbic acid ion-pair complex (LAM-SA) (w/w), and 10 % isopropyl myristate (IPM) (w/w), with a patch thickness of 70 μm, achieving an erythema index of 188 for rabbit skin and 117–187 for human skin (264 for rabbit skin and 110–260 for human skin in the absence of sorbic acid (SA)). In vivo rabbit and human skin erythema analysis and H&E staining verified that the optimized ion-pair patch effectively reduced skin irritation. Drug distribution experiments in the skin, ATR-FTIR, and molecular simulation were used to characterize the mechanism by which the ion-pair reduced skin irritation. Excessive accumulation of LAM in the epidermis induced secondary structural changes in keratin, resulting in skin barrier damage and inflammatory response. The formation of the LAM-SA ion pair altered physicochemical properties of LAM, reducing drug retention in the epidermis and, thereby, reducing skin irritation. This study demonstrated the potential of the ion-pair strategy to improve the safety of transdermal drug delivery system (TDDS) and provided a means for reducing skin irritation caused by the active pharmaceutical ingredient (API) itself.

本研究的目的是利用离子对策略开发一种左旋氨氯地平（LAM）长效透皮贴片，以减少局部应用左旋氨氯地平引起的皮肤刺激，并探索改善皮肤刺激的机制。通过猪体外透皮实验和兔子体内皮肤刺激试验，对制剂进行了优化。获得的配方由聚（2-乙基己基丙烯酸酯-N-乙烯基-2-吡咯烷酮-N-（2-羟乙基）丙烯酰胺）（PENH）作为粘合基质，13.00 % 左旋氨氯地平-山梨酸离子对复合物（LAM-SA）（重量比）和 10 % 肉豆蔻酸异丙酯（IPM）（重量比），贴片厚度为 70 μm，兔皮肤的红斑指数为 188，人皮肤的红斑指数为 117-187（在没有山梨酸（SA）的情况下，兔皮肤的红斑指数为 264，人皮肤的红斑指数为 110-260）。体内兔皮和人皮红斑分析和 H&E 染色证实，优化的离子对贴片有效降低了皮肤刺激性。药物在皮肤中的分布实验、ATR-傅立叶变换红外光谱和分子模拟被用来描述离子对降低皮肤刺激性的机制。LAM 在表皮中的过度积聚会诱发角蛋白的继发性结构变化，导致皮肤屏障受损和炎症反应。LAM-SA 离子对的形成改变了 LAM 的物理化学特性，减少了药物在表皮中的滞留，从而减轻了对皮肤的刺激。这项研究证明了离子对策略在提高透皮给药系统（TDDS）安全性方面的潜力，并为减少活性药物成分（API）本身对皮肤的刺激提供了一种方法。

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引用次数: 0

Accelerated removal of solvent residuals from PLGA microparticles by alcohol vapor-assisted fluidized bed drying 用酒精蒸汽辅助流化床干燥法加速去除聚乳酸乙烯-丙烯酸（PLGA）微粒中的溶剂残留。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-09-20 DOI: 10.1016/j.ijpharm.2024.124737

The removal of residual solvents from biodegradable poly(D,L-lactide-co-glycolide) (PLGA) microparticles by fluidized bed drying was investigated. Microparticles were prepared by the O/W solvent extraction/evaporation method and the influence of various process and formulation parameters on the secondary drying was studied. PLGA microparticles and films were characterized for residual organic solvent and water content, recrystallisation, surface morphology, drug loading and in-vitro release of the drugs dexamethasone and risperidone. While alcohol-free fluidized bed drying decreased the residual dichloromethane content only from about 7 % (w/w) to 6.4 % (w/w) (18 °C) or 3.2 % (w/w) (35 °C) within 24 h, 140 mg/L methanol vapor in purge gas facilitated almost complete removal of dichloromethane or ethyl acetate from microparticles (0–0.11 % (w/w) after 6 h). By controlling the alcohol concentration and temperature of the purge gas, the alcohol absorption and complete removal was controlled. Risperidone increased the methanol absorption enhancing the plasticization. A high initial residual water content was identified to promote aggregation and was eliminated by starting fluidized bed drying without alcohol. Alcohol vapor-assisted fluidized bed drying accelerated microparticle manufacturing without affecting the redispersibility, the drug loading and the in-vitro release of risperidone and dexamethasone.

研究了通过流化床干燥去除可生物降解的聚（D,L-乳酸-共聚乙二醇）（PLGA）微粒中的残留溶剂。微粒采用 O/W 溶剂萃取/蒸发法制备，研究了各种工艺和配方参数对二次干燥的影响。对 PLGA 微颗粒和薄膜的残留有机溶剂和水含量、再结晶、表面形态、药物负载以及药物地塞米松和利培酮的体外释放进行了表征。无醇流化床干燥在24小时内仅将二氯甲烷的残留量从约7%（w/w）降至6.4%（w/w）（18 °C）或3.2%（w/w）（35 °C），而净化气体中的140毫克/升甲醇蒸汽几乎能完全去除微颗粒中的二氯甲烷或乙酸乙酯（6小时后为0--0.11%（w/w））。通过控制酒精浓度和净化气体的温度，可以控制酒精的吸收和完全去除。利培酮增加了甲醇的吸收，提高了塑化效果。研究发现，高初始残余水含量会促进聚结，而在不使用酒精的情况下开始流化床干燥，则可消除残余水含量。酒精蒸汽辅助流化床干燥加速了微粒的制造，但不会影响利培酮和地塞米松的可再分散性、药物负载和体外释放。

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引用次数: 0

Effect of iontophoresis on dacarbazine cutaneous delivery for melanoma topical treatment 电离子渗透对黑色素瘤局部治疗中达卡巴嗪皮肤给药的影响

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-09-19 DOI: 10.1016/j.ijpharm.2024.124730

Dacarbazine (DTIC) is the drug of choice for melanoma treatment, but its systemic administration is related to several adverse effects. Here, DTIC topical delivery stimulated by iontophoresis is proposed to overcome such drawbacks. Hence, this work analyzed the impact of anodal iontophoresis on DTIC cutaneous delivery to provide an innovative topical alternative for melanoma treatment. The electrical stability of the drug was evaluated prior to the iontophoretic experiments, which demonstrated the need to add an antioxidant to the drug formulation. DTIC cutaneous permeation was evaluated in vitro for 6 h using three current densities (0.10, 0.25, and 0.50 mA/cm²). In addition, the effect of DTIC against skin cancer cells (MeWo and WM164) was investigated for 72 h of exposure to the drug. Iontophoresis stimulated skin drug permeation compared to the passive control. However, the antioxidant presence reduced DTIC permeation under the lower currents of 0.10 and 0.25 mA/cm², which was compensated by increasing the current density to 0.50 mA/cm². At 0.50 mA/cm², iontophoresis enhanced topical cutaneous drug permeation 7-fold (p < 0.05) compared to the passive control. DTIC showed a concentration-dependent antiproliferative effect on melanoma cell lines. Thus, iontophoresis intensifies DTIC skin penetration in concentrations that can reduce cell viability and induce cell death. In conclusion, DTIC cutaneous delivery mediated by iontophoresis is a promising approach for treating melanomas and other skin tumors.

达卡巴嗪（DTIC）是治疗黑色素瘤的首选药物，但全身用药会产生一些不良反应。为了克服这些弊端，有人提出了利用离子透入技术刺激 DTIC 局部给药的方法。因此，本研究分析了阳极离子透入对 DTIC 皮肤给药的影响，从而为黑色素瘤治疗提供一种创新的局部给药替代方法。在进行离子渗透实验之前，对药物的电稳定性进行了评估，结果表明有必要在药物配方中添加抗氧化剂。在体外使用三种电流密度（0.10、0.25 和 0.50 mA/cm2）对 DTIC 的皮肤渗透性进行了 6 小时的评估。此外，还研究了 DTIC 与皮肤癌细胞（MeWo 和 WM164）接触 72 小时后的效果。与被动对照组相比，离子透入疗法刺激了皮肤的药物渗透。然而，在 0.10 和 0.25 mA/cm2 的较低电流下，抗氧化剂的存在会降低 DTIC 的渗透，而将电流密度提高到 0.50 mA/cm2 则可弥补这一不足。在 0.50 毫安/平方厘米的电流密度下，电离子渗透将局部皮肤药物渗透提高了 7 倍（p

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引用次数: 0

Preparation of tenofovir amibufenamide fumarate spherical particles to improve tableting performance and sticking propensity by designing a spherical crystallization process 通过设计球形结晶工艺制备富马酸替诺福韦-阿米布非那胺球形颗粒，以改善压片性能和粘附倾向。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-09-19 DOI: 10.1016/j.ijpharm.2024.124709

Tenofovir amibufenamide fumarate (TMF) is the first oral drug developed in Asia for the treatment of adult patients with chronic viral hepatitis B, however, further applications are limited by poor tableting performance and high sticking propensity. In this work, the spherulitic growth process of TMF has been designed and explored with the help of molecular dynamics simulation and process analysis technologies (ATR-FTIR, FBRM and EasyViewer). The spherical particles with high bulk density, good flowability and uniform particle size distribution are prepared by a simple quenching process. More importantly, experimental results show that spherical particles have higher average tensile strength (100.8% increase), higher plastic deformability and lower amount of punch sticking (87.4% decrease in 30 tablets) compared to the commercial powder products. These contributions not only shed light on the design principle of drug spherulitic growth processes, but also provide guidance for the manufacture of high-quality tablet products.

富马酸替诺福韦酯（TMF）是亚洲开发的第一种口服药物，用于治疗成年慢性乙型病毒性肝炎患者。本研究利用分子动力学模拟和过程分析技术（ATR-FTIR、FBRM 和 EasyViewer）设计并探索了 TMF 的球形生长过程。通过简单的淬火工艺，制备出了体积密度高、流动性好且粒度分布均匀的球形颗粒。更重要的是，实验结果表明，与商业粉末产品相比，球形颗粒具有更高的平均拉伸强度（增加 100.8%）、更高的塑性变形能力和更低的冲孔粘连量（30 片减少 87.4%）。这些贡献不仅揭示了药物球形生长过程的设计原理，还为生产高质量的片剂产品提供了指导。

引用次数: 0

Development and integration of a continuous horizontal belt filter into drug production procedure 开发连续式水平带式过滤机并将其纳入药品生产程序。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

International Journal of Pharmaceutics

Pub Date : 2024-09-19 DOI: 10.1016/j.ijpharm.2024.124729

In the pharmaceutical industry, filtration is traditionally carried out in batch mode. However, with the spread of continuous technologies, there is an increasing demand for robust continuous filtration strategies suitable for processing suspensions produced in continuous crystallizers. Accordingly, this study aimed to investigate a lab-scale horizontal conveyor belt filtration approach for pharmaceutical separation purposes for the first time. The newly developed continuous horizontal belt filter (CHBF) was tested under different systems (microcrystalline cellulose (MCC)/water, lactose/ethanol and acetylsalicylic acid (ASA)/water) and diverse conditions. Filtration was robust using a well-defined unimodal particle size distribution MCC in water system, where the residual moisture content varied within narrow limits of 45–52% independently from the process conditions. Besides, the residual moisture content highly depended on the applied solvent and particle size. It could be reduced to below 2% by processing the suspensions of either a volatile solvent (lactose in ethanol) or an aqueous slurry of a large particle size ASA. Finally, the CHBF was connected to a mixed suspension mixed product removal (MSMPR) or a plug flow crystallizer (PFC). The residual moisture content of the CHBF-filtered ASA product and operation characteristics (onset of steady-state) were evaluated in both continuous crystallizer-filter systems. The MSMPR-CHBF system operated with a longer startup period. The size of the in situ-produced crystals was of a similar order magnitude in both systems, resulting in a similar residual moisture content (around 20%). Overall, the tested continuous filter was robust, did not modify the crystal morphology in the examined experimental range, and could be effectively integrated with continuous crystallizers.

在制药行业，过滤传统上是以间歇模式进行的。然而，随着连续技术的普及，对适用于处理连续结晶器生产的悬浮液的强大连续过滤策略的需求日益增加。因此，本研究旨在首次研究一种用于制药分离的实验室规模水平传送带过滤方法。在不同系统（微晶纤维素（MCC）/水、乳糖/乙醇和乙酰水杨酸（ASA）/水）和不同条件下，对新开发的连续水平带式过滤器（CHBF）进行了测试。在水体系中使用明确的单模态粒度分布的 MCC，过滤效果很好，残余水分含量在 45-52% 的狭窄范围内变化，不受工艺条件的影响。此外，残余水分含量在很大程度上取决于所使用的溶剂和颗粒大小。通过处理挥发性溶剂（乙醇中的乳糖）悬浮液或大粒径 ASA 的水性浆液，可将残余水分含量降至 2% 以下。最后，将 CHBF 连接到混合悬浮液混合产品去除装置 (MSMPR) 或塞流结晶器 (PFC)。在这两种连续结晶器-过滤器系统中，对经 CHBF 过滤的 ASA 产品的残余水分含量和运行特性（稳态开始）进行了评估。MSMPR-CHBF 系统的启动时间较长。两个系统原位生成的晶体大小相近，因此残余水分含量也相近（约 20%）。总之，测试的连续式过滤器性能稳定，在实验范围内不会改变晶体形态，并能与连续式结晶器有效集成。

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